[go: up one dir, main page]

WO1996014308A1 - Derives du taxane - Google Patents

Derives du taxane Download PDF

Info

Publication number
WO1996014308A1
WO1996014308A1 PCT/EP1995/004302 EP9504302W WO9614308A1 WO 1996014308 A1 WO1996014308 A1 WO 1996014308A1 EP 9504302 W EP9504302 W EP 9504302W WO 9614308 A1 WO9614308 A1 WO 9614308A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
group
aza
deoxy
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1995/004302
Other languages
English (en)
Inventor
Maria Menichincheri
Walter Ceccarelli
Marina Ciomei
Domenico Fusar Bassini
Nicola Mongelli
Ermes Vanotti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Italia SRL
Original Assignee
Pharmacia SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB9422245A external-priority patent/GB9422245D0/en
Priority claimed from GBGB9511475.7A external-priority patent/GB9511475D0/en
Priority claimed from GBGB9521168.6A external-priority patent/GB9521168D0/en
Application filed by Pharmacia SpA filed Critical Pharmacia SpA
Priority to EP95938390A priority Critical patent/EP0738265A1/fr
Priority to US08/663,080 priority patent/US5719177A/en
Priority to JP8515041A priority patent/JPH09509431A/ja
Publication of WO1996014308A1 publication Critical patent/WO1996014308A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to new taxane derivatives
  • the taxane family of diterpenes includes Paclitaxel (also called Paclitaxel).
  • paclitaxel is a very potent anticancer drug
  • the present invention provides taxane derivatives modified
  • the invention provides taxane derivatives of
  • R represents a hydrogen atom or a hydroxy group, or taken together with R 3 , a bond;
  • R a and R c are hydrogens and R is hydroxy, or (ii) R a and R b taken together form a bond and R c is hydrogen, or
  • R a is hydrogen atom and R b and R c taken together form
  • R b is azido or amino group and R c is hydrogen atom;
  • R x represents a hydrogen atom, a hydroxy group or a residue
  • R' and R" are each independently Ci-Cg alkyl
  • N , as pure E or pure Z isomers or as a mixture of both E and
  • R 4 is a Ci-Cg alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl group or a phenyl or heteroaryl group, optionally substituted with one,
  • Ci-C 6 alkyl a halogen atom and Ci-C 6 alkyl
  • R 5 is -COOR' ' ' or -COR' ' ' , or CONHR' ' ' wherein R' ' ' is Ci-
  • Cg alkyl preferably tert-butyl or n-pentyl, C 2 -C 6 alkenyl, preferably 1-methyl-l-propenyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkynyl
  • alkoxy and -CF 3 groups - or a group of the formula Y or Y-O- wherein Y is as defined above,-
  • R 2 represents a group of the formula B-NH- wherein B
  • n is 0 or l
  • R 3 represents hydrogen, or, taken with R , a bond
  • the R 2 substituent may be in the R or S configuration.
  • R 2 substituent may be in both the R and S
  • Ci-Cg alkyl group is a straight or branched alkyl group
  • Ci-C 4 alkyl group such as methyl, ethyl, n-propyl,
  • a C 2 -C 6 alkenyl group is a straight or branched
  • alkenyl group preferably a C 2 -C 5 alkenyl group such as vinyl
  • a C 3 -C 6 cycloalkyl group is a saturated
  • a halogen is preferably fluorine, chlorine, bromine or
  • the heteroaryl group is preferably a 3- to 6-membered
  • heterocycyl ring may be a 3-, 4-, 5- or 6- membered such ring.
  • a cycloalkyl group is generally a said C 3 -C 6 cycloalkyl group.
  • An aryl group is generally phenyl or
  • heterocyclyl groups are pyrrolyl, pyrazolyl,
  • imidazolyl triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,thienyl, furyl,
  • a C 2 -C 6 alkenediyl chain can be a straight or branched
  • the C 2 -C 6 alkynyl group is a
  • a C ⁇ -C 6 alkoxy group can be a straight chain or
  • branched alkoxy group preferably a C ⁇ ⁇ C 4 alkoxy group such as
  • Preferred compounds of the invention are taxane derivatives
  • R a and R c are hydrogen atoms and R b is hydroxy, R x
  • R' and R" are each independently C ⁇ -C 4 alkyl, C 2 -C 3 alkenyl, C 3 -C 6 cycloalkyl, C 2 -C 5 alkynyl or a phenyl group,
  • A represents: - a hydrogen atom, a hydroxy, methoxy, acetoxy, amino,
  • R 4 is a Ci-C- alkyl, C 2 -C 5 alkenyl, C 3 -C 6 cycloalkyl group or a
  • R 5 is -COOR' ' ' or -COR' ' ' or -CONHR' ' ' wherein R' " is Ci ⁇ C 4
  • alkyl C 2 -C 5 alkenyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkynyl or a
  • phenyl group optionally substituted with one, two or three
  • substituents which may be the same or different and which are selected from a halogen atom and C ⁇ C 4 alkyl, C ⁇ C 4 alkoxy and
  • R 2 represents a group of the formula -NH-B wherein B
  • n 0 or 1
  • R 3 represents hydrogen, taken together with R, a bond.
  • Ri is preferably a hydrogen atom, a hydroxy group or an acetoxy
  • R 3 is preferably a hydrogen atom.
  • R 2 preferably
  • B is preferably the
  • R 4 is preferably phenyl or 2-furyl.
  • R 5 is benzoyl or t- butoxycarbonyl group.
  • the pharmaceutically acceptable salts are typically those salts formed with pharmaceutically acceptable acids, both inorganic acids like hydrochloric, hydrobromic, sulfuric, phosphoric, diphosphoric, or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid.
  • inorganic acids like hydrochloric, hydrobromic, sulfuric, phosphoric, diphosphoric, or nitric acid
  • organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid.
  • Further preferred compounds of the invention are: 13-aza-paclitaxel, 13-aza-10-desacetoxy paclitaxel, 13-aza-10- desacetyl paclitaxel, 13-aza-taxotere, l3-aza-10-deoxy- taxotere, 10 deacetoxy-13-deoxy-13-imino paclitaxel, 10,13 dideoxy-13-imino taxotere, 13-deoxy-13-imino paclitaxel, 13- deoxy-13-imino taxotere, 10-deacetoxy-13-deoxy-13, 14 ene-13- aza-paclitaxel, 13-deoxy-13, 14 ene-13-aza-paclitaxel, 10,13- dideoxy-13, 14 ene-13 aza-taxotere, 13,14 ene-13-aza-taxotere.
  • the suffix "aza" means that the oxygen atom of the substituent at position 13 of the taxol structure has been replaced with an NH residue.
  • the present invention also provides a process for the preparation of taxane derivatives of formula I as above defined.
  • the following scheme illustrates the reaction sequence:
  • the process comprises, in a first step (a) , the reaction of
  • R 1# R a and R c are as defined above and R' b or has the same meanings of R b except for OH or NH 2 , either represents a
  • trialkylsilyl or other hydroxy protecting groups such as phenyldimethylsilyl, triisopropylsilyl, t-
  • ammonia or an ammonium salt such as ammonium chloride
  • acylating agent such as acetic anhydride or
  • step (c) the resultant 13-oxime of formula IV may be
  • Nickel, Pt or Pd to give the hydroxylamino derivatives of the
  • the compound of formula IVb may be oxidized in the
  • organic peracid such as m-chloro perbenzoic acid
  • step (d) the compound of formula IV, IVa, ,- IVc, V or
  • VI can optionally be reduced to give the amino derivative of formula IX using standard procedures (e.g. reduction with
  • step (e) the C-13 derivatives of formula IV, IVa, IVb, VII, VIII or IX can be acylated with an appropriately
  • R A is a hydroxy protecting group, preferably wherein R A is a hydroxy protecting group, preferably
  • R B is H or CH 3
  • R c is CH 3 or an optionally substituted phenyl group
  • R D is an
  • R c and R 4 and R 5 are as defined above, in the presence of a condensing agent such
  • the deprotection is carried out for example by
  • protecting group is removed in acidic conditions, such as with
  • Xb, Xc and Xd are known or may be carried out according to known methods; for example 7-triethylsilyl-3-keto-baccatin
  • the present invention also provides a
  • R 7 is hydrogen
  • the compound of formula la and the pharmaceutically acceptable salt thereof may be prepared by a process which comprises:
  • R 1; R a , R b ' , R c and R 7 are as above defined except
  • Step (a) may be effected by using standard conditions such as
  • Step (b) can be carried out as described above for step (f)
  • the appropriate acylating agent may be selected from the group
  • activated/protected carboxylic acid derivatives such as
  • the cytotoxic activity of the compounds may be evaluated on
  • the mode of action of the compound may also be
  • Calf brain tubulin was prepared by two cycles of
  • MAB 0.1 M MES, 2.5 mM EGTA, 0.5 mM MgS0 4
  • the cuvette (1 cm path) containing tubulin (lmg/ml) and 1
  • antitumour agents They may also be useful for the preparation of other antitumour agents.
  • a human or animal may also be useful for the preparation of other antitumour agents.
  • a human or animal may also be useful for the preparation of other antitumour agents.
  • suffering from a tumour may thus be treated by a method which
  • the condition of the human or animal may thereby be improved.
  • tumours examples include sarcomas,
  • Taxane adenocarcinomas.
  • salts thereof can be used to treat ovarian cancer
  • platinum-resistant ovarian cancer metastatic breast cancer, non-small cell lung cancer, and head and neck cancer.
  • invention also provides a pharmaceutical composition which
  • composition of the invention is usually prepared following conventional methods and is administered in a
  • Administration can be made by
  • antitumour agents such as intravenous, intramuscular or subcutaneous
  • active compound may be, e.g., dissolved in a vehicle
  • person may range from about O.Olg to about lg per day.
  • the (E) -oxime was isolated as a white solid (lOOmg, 38% yield) .
  • isomer 1 (24mg, 15%)
  • isomer 2 (31mg, 19%) .
  • Raney-nickel aqueous slurry 50mg was added. The reaction mixture was stirred at room temperature for 3 hours, then was
  • reaction mixture was stirred for 2 hours at 0°C.
  • the reaction mixture was poured into ice-water and extracted with
  • reaction mixture was poured into cold water and extracted
  • the title compound may be in equilibrium with the following
  • reaction mixture was stirred at 0°C for 2 hours,- then it was poured into ice-water and extracted with ethyl acetate.
  • silica gel (eluant: n-hexane/ethyl acetate 1:1) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)

Abstract

L'invention se rapporte à des dérivés du taxane modifiés à la position 13 du squelette des dérivés du taxane (numérotage du taxol) de la formule (I) dans laquelle R, Ra, Rb, Rc, et R1, R2, R3 représentent des résidus organiques appropriés pouvant être utilisés comme agents antitumoraux
PCT/EP1995/004302 1994-11-04 1995-11-02 Derives du taxane Ceased WO1996014308A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95938390A EP0738265A1 (fr) 1994-11-04 1995-11-02 Derives du taxane
US08/663,080 US5719177A (en) 1994-11-04 1995-11-02 Taxane derivatives
JP8515041A JPH09509431A (ja) 1994-11-04 1995-11-02 タキサン誘導体

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9422245A GB9422245D0 (en) 1994-11-04 1994-11-04 Taxane derivatives
GBGB9511475.7A GB9511475D0 (en) 1995-06-07 1995-06-07 Taxane derivatives
GB9521168.6 1995-10-16
GBGB9521168.6A GB9521168D0 (en) 1995-10-16 1995-10-16 Taxane derivatives
GB9422245.2 1995-10-16
GB9511475.7 1995-10-16

Publications (1)

Publication Number Publication Date
WO1996014308A1 true WO1996014308A1 (fr) 1996-05-17

Family

ID=27267459

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/004302 Ceased WO1996014308A1 (fr) 1994-11-04 1995-11-02 Derives du taxane

Country Status (4)

Country Link
US (2) US5719177A (fr)
EP (1) EP0738265A1 (fr)
JP (1) JPH09509431A (fr)
WO (1) WO1996014308A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5719177A (en) * 1994-11-04 1998-02-17 Pharmacia S.P.A. Taxane derivatives
WO2001007040A1 (fr) * 1999-07-28 2001-02-01 Kobe Natural Products & Chemicals Co., Ltd. Agents anticancereux surmontant la multiresistance et leur procede d'obtention
EP1980557A2 (fr) 2002-09-10 2008-10-15 Indena S.P.A. Dérives de taxanes fonctionnalises en position 14 et procède de préparation
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4502338B2 (ja) * 1999-09-17 2010-07-14 株式会社横浜国際バイオ研究所 タキソイド化合物の製造法
HK1049787B (en) 1999-10-01 2014-07-25 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
EP1301500B1 (fr) 2000-06-22 2007-11-21 Nitromed, Inc. Taxanes nitroses et nitrosyles, compositions et procedes d'utilisation
US7772177B2 (en) 2005-05-18 2010-08-10 Aegera Therapeutics, Inc. BIR domain binding compounds
AU2007250443B2 (en) 2006-05-16 2013-06-13 Pharmascience Inc. IAP BIR domain binding compounds
EP2534170B1 (fr) 2010-02-12 2017-04-19 Pharmascience Inc. Composés de liaison au domaine iap bir
WO2013119864A1 (fr) 2012-02-07 2013-08-15 University Of Central Florida Research Foundation, Inc. Renforcement de la sensibilité au taxane de cellules cancéreuses
WO2015149001A1 (fr) 2014-03-27 2015-10-01 The Brigham And Women's Hospital, Inc. Conjugués de médicaments activés métaboliquement pour vaincre la résistance dans une thérapie du cancer

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9422245D0 (en) 1994-11-04 1994-12-21 Erba Carlo Spa Taxane derivatives
GB9511475D0 (en) 1995-06-07 1995-08-02 Pharmacia Spa Taxane derivatives
US5719177A (en) * 1994-11-04 1998-02-17 Pharmacia S.P.A. Taxane derivatives
GB9521168D0 (en) 1995-10-16 1995-12-20 Pharmacia Spa Taxane derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANI,M. ET AL.: "PLANT ANTITUMOR AGENTS.VI.THE ISOLATION AND STRUCTURE OF TAXOL", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 93, 7 April 1971 (1971-04-07), DC US, pages 2325 - 2327 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5719177A (en) * 1994-11-04 1998-02-17 Pharmacia S.P.A. Taxane derivatives
WO2001007040A1 (fr) * 1999-07-28 2001-02-01 Kobe Natural Products & Chemicals Co., Ltd. Agents anticancereux surmontant la multiresistance et leur procede d'obtention
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
EP1980557A2 (fr) 2002-09-10 2008-10-15 Indena S.P.A. Dérives de taxanes fonctionnalises en position 14 et procède de préparation
EP2077264A2 (fr) 2002-09-10 2009-07-08 INDENA S.p.A. Dérivés de taxanes et procédé de préparation
EP2264019A1 (fr) 2002-09-10 2010-12-22 Indena S.p.A. Produits intermediaire pour la préparation des dérives de taxanes
EP2281820A2 (fr) 2002-09-10 2011-02-09 Indena S.p.A. Dérives de taxanes et procède de préparation
EP2298754A1 (fr) 2002-09-10 2011-03-23 Indena S.p.A. Procédé de préparation pour les dérivés de taxanes
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8003812B2 (en) 2004-02-13 2011-08-23 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

Also Published As

Publication number Publication date
US5719177A (en) 1998-02-17
JPH09509431A (ja) 1997-09-22
EP0738265A1 (fr) 1996-10-23
US5912263A (en) 1999-06-15

Similar Documents

Publication Publication Date Title
RU2134688C1 (ru) Полусинтетический таксан, промежуточные соединения, способы получения и фармацевтическая композиция
US5395850A (en) 6,7-epoxy paclitaxels
Kingston et al. The chemistry of taxol and related taxoids
US5380751A (en) 6,7-modified paclitaxels
CA2109861C (fr) Paclitaxels modifies en 6,7
US5440056A (en) 9-deoxotaxane compounds
WO1996014308A1 (fr) Derives du taxane
US20160331718A1 (en) 9, 10-alpha, alpha-oh-taxane analogs and method for production thereof
HU215839B (hu) Új, furil- és tienil-csoporttal szubsztituált taxánszármazékok és hatóanyagként ilyen vegyületeket tartalmazó gyógyszerkészítmények, valamint eljárás előállításukra
CA2099211A1 (fr) 7,8-cyclopropataxanes
HU211824A9 (en) Baccatine iii derivatives
JPH08503218A (ja) ブテニル置換タキサンおよび組成物
CA2253912C (fr) Derives de taxane, leur preparation et formulations les contenant
JPH08503219A (ja) アルキル置換側鎖を有するタキサンおよびそれを含有する薬剤組成物
WO1999037631A1 (fr) Nouveaux composes de taxaneterpine
EP0738266A1 (fr) Derives de taxane
GB2296239A (en) Taxane derivatives modified at 6 and 7 positions for use as antitumour agents
GB2289277A (en) Taxane derivatives
EP0394135A1 (fr) Noveaux dérivés macrolides, leur procédé de préparation et leur compositions pharmaceutiques qui les contiennent
Cheng et al. High Regio-and Stereoselectivity in Facile One-Pot Conversion of Taxolds to the Primary Alcohols: Precursors for the Synthesis of 4-Deacetoxypacliltaxel and Analogues
US8697892B2 (en) Taxane compounds, compositions and methods
JPH08295682A (ja) バッカチン誘導体及びその製法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

WWE Wipo information: entry into national phase

Ref document number: 08663080

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1995938390

Country of ref document: EP

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWP Wipo information: published in national office

Ref document number: 1995938390

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995938390

Country of ref document: EP